Parkinson’s disease patient-specific neuronal networks carrying the LRRK2 G2019S mutation unveil early functional alterations that predate neurodegeneration

A deeper understanding of early disease mechanisms occurring in Parkinson's disease (PD) is needed to reveal restorative targets. Here we report that human induced pluripotent stem cell (iPSC)-derived dopaminergic neurons (DAn) obtained from healthy individuals or patients harboring LRRK2 PD-ca...

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Detalles Bibliográficos
Autores: Carola, Giulia, Malagarriga, Daniel, Calatayud Aristoy, Carles, Pons-Espinal, Meritxell, Blasco Agell, Lucas, Richaud-Patin, Yvonne, Fernandez-Carasa, Irene, Baruffi, Valentina, Beltramone, Silvia, Molina, Elsa, Dell’Era, Patrizia, Toledo Aral, Juan J., Tolosa, Eduardo, Muotri, Alysson R., García Ojalvo, Jordi, Soriano i Fradera, Jordi, Raya Chamorro, Ángel, Consiglio, Antonella
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/179150
Acceso en línea:https://hdl.handle.net/2445/179150
Access Level:acceso abierto
Palabra clave:Malaltia de Parkinson
Mutació (Biologia)
Enginyeria genètica
Parkinson's disease
Mutation (Biology)
Genetic engineering
Descripción
Sumario:A deeper understanding of early disease mechanisms occurring in Parkinson's disease (PD) is needed to reveal restorative targets. Here we report that human induced pluripotent stem cell (iPSC)-derived dopaminergic neurons (DAn) obtained from healthy individuals or patients harboring LRRK2 PD-causing mutation can create highly complex networks with evident signs of functional maturation over time. Compared to control neuronal networks, LRRK2 PD patients' networks displayed an elevated bursting behavior, in the absence of neurodegeneration. By combining functional calcium imaging, biophysical modeling, and DAn-lineage tracing, we found a decrease in DAn neurite density that triggered overall functional alterations in PD neuronal networks. Our data implicate early dysfunction as a prime focus that may contribute to the initiation of downstream degenerative pathways preceding DAn loss in PD, highlighting a potential window of opportunity for pre-symptomatic assessment of chronic degenerative diseases.

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